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S Sokol

Publications and source records attributed to S Sokol.

At least 19 recordsLinked to original sources
PubMed2001

Head inducer Dickkopf-1 is a ligand for Wnt coreceptor LRP6.

BACKGROUND: Dickkopf-1 (Dkk-1) is a head inducer secreted from the vertebrate head organizer and induces anterior development by antagonizing Wnt signaling. Although several families of secreted antagonists have been shown to inhibit Wnt signal transduction by binding to Wnt, the molecular mechanism of Dkk-1 action is unknown. The Wnt family of secreted growth factors initiates signaling via the Frizzled (Fz) receptor and its candidate coreceptor, LDL receptor-related protein 6 (LRP6), presumably through Fz-LRP6 complex formation induced by Wnt. The significance of the Fz-LRP6 complex in signal transduction remains to be established. RESULTS: We report that Dkk-1 is a high-affinity ligand for LRP6 and inhibits Wnt signaling by preventing Fz-LRP6 complex formation induced by Wnt. Dkk-1 binds neither Wnt nor Fz, nor does it affect Wnt-Fz interaction. Dkk-1 function in head induction and Wnt signaling inhibition strictly correlates with its ability to bind LRP6 and to disrupt the Fz-LRP6 association. LRP6 function and Dkk-1 inhibition appear to be specific for the Wnt/Fz beta-catenin pathway. CONCLUSIONS: Our results demonstrate that Dkk-1 is an LRP6 ligand and inhibits Wnt signaling by blocking Wnt-induced Fz-LRP6 complex formation. Our findings thus reveal a novel mechanism for Wnt signal modulation. LRP6 is a Wnt coreceptor that appears to specify Wnt/Fz signaling to the beta-catenin pathway, and Dkk-1, distinct from Wnt binding antagonists, may be a specific inhibitor for Wnt/beta-catenin signaling. Our findings suggest that Wnt-Fz-LRP6 complex formation, but not Wnt-Fz interaction, triggers Wnt/beta-catenin signaling.

Animals↗
PubMed2001

Myoglobin levels at 12 hours identify patients at low risk for 30-day mortality after thrombolysis in acute myocardial infarction: a Thrombolysis in Myocardial Infarction 10B substudy.

OBJECTIVE: We sought to identify, by use of serum cardiac markers, patients at low risk for 30-day mortality after ST-segment elevation myocardial infarction. BACKGROUND: Baseline cardiac markers are currently used to identify patients at increased risk for short-term events. We hypothesized that serum markers measured after treatment could identify patients at low risk for 30-day mortality. METHODS: A total of 839 patients from the Thrombolysis in Myocardial Infarction (TIMI) 10B study had myoglobin, cardiac-specific troponin-I, creatine kinase (CK)-MB measurements at the following time points; baseline, 90 minutes, and 3 and 12 hours after thrombolysis. By use of receiver operating characteristic analysis, thresholds were derived to predict 30-day mortality with at least 95% negative predictive value. RESULTS: Ninety minutes after thrombolysis myoglobin was superior to troponin-I or CK-MB in identifying patients at low risk for mortality. The 30-day mortality for 12-hour myoglobin < or = 239 ng/mL was 1.4% compared with 9.1% for levels > 239 ng/mL (P < .001). For 12-hour troponin-I (threshold 81.5 ng/mL), mortality was 1.9% versus 6.6% (P = .001) if above threshold; similarly for CK-MB at 12 hours (threshold 191 ng/mL) it was 3.3% versus 7.9% (P = .02). Multivariate analysis of baseline and posttreatment cardiac markers, age, sex, infarct artery location, and 90-minute TIMI flow grade identified only 12-hour myoglobin among the cardiac markers as independently predicting a low 30-day mortality (odds ratio 0.11, 95% confidence interval 0.02-0.50, P < .004). CONCLUSION: Serum cardiac markers can identify greater than two thirds of patients at low risk for 30-day mortality. A low 12-hour myoglobin level (< or = 239 ng/mL in this substudy) identifies such patients at low risk and could potentially assist in early risk stratification and triage after ST-segment elevation myocardial infarction.

Aged↗
PubMed2000

A role for Wnts in morpho-genesis and tissue polarity.

Recent studies have shown that secreted Wnt proteins control morphogenetic movements in fish and frog embryos. The analysis of Dishevelled, a cytoplasmic mediator of Wnt signalling, reveals unexpected similarity between gastrulation in vertebrates and polarization of cells in Drosophila epithelia.

Adaptor Proteins, Signal Transducing↗
PubMed2000

Interaction of dishevelled and Xenopus axin-related protein is required for wnt signal transduction.

Signaling by the Wnt family of secreted proteins plays an important role in animal development and is often misregulated in carcinogenesis. Wnt signal transduction is controlled by the rate of degradation of beta-catenin by a complex of proteins including glycogen synthase kinase 3 (GSK3), adenomatous polyposis coli, and Axin. Dishevelled is required for Wnt signal transduction, and its activation results in stabilization of beta-catenin. However, the biochemical events underlying this process remain largely unclear. Here we show that Xenopus Dishevelled (Xdsh) interacts with a Xenopus Axin-related protein (XARP). This interaction depends on the presence of the Dishevelled-Axin (DIX) domains in both XARP and Xdsh. Moreover, the same domains are essential for signal transduction through Xdsh. Finally, our data point to a possible mechanism for signal transduction, in which Xdsh prevents beta-catenin degradation by displacing GSK3 from its complex with XARP.

Adaptor Proteins, Signal Transducing↗
PubMed1999

FGF is required for posterior neural patterning but not for neural induction.

Fibroblast growth factor (FGF) has been implicated in a variety of developmental processes including posterior mesoderm and neural patterning. Previous work has led to contradictory roles for FGF in neural induction and anteroposterior neural patterning. Launay et al. (Development 122, 869-880, 1996) suggested a requirement for FGF in anterior neural induction. In contrast, Kroll and Amaya (Development 122, 3173-3183, 1996) and Bang et al. (Development 124, 2075-2085, 1997) proposed that FGF is not required for early neural patterning. Here we use a loss-of-function assay to examine whether FGF is required for neural patterning in three experimental situations: (i) in Xenopus early embryos, (ii) in embryonic explants consisting of presumptive dorsal mesoderm and neurectoderm (Keller explants), and (iii) in explants of dorsal ectoderm and posterior mesoderm in which FGF signaling is specifically blocked in the ectoderm. When cultured until tailbud stages, Keller explants develop neural tissue with normal anteroposterior pattern. Overexpression of the dominant-negative FGF receptor (XFD) in Keller explants inhibited the posterior neural markers En-2, Krox-20, and HoxB9, but not the panneural marker nrp-1 and the anterior neurectodermal markers XAG-1 and Xotx-2. Similar results were seen in whole embryos, but only when XFD RNA was targeted to both the dorsal and lateral regions. In contrast, addition of FGF to Keller explants resulted in a shift of the midbrain-hindbrain boundary marker En-2 to a more anterior position normally fated to become cement gland. We also determined whether FGF is required specifically by the neurectoderm for anteroposterior neural patterning. Recombinants of dorsal ectoderm and posterior mesoderm were made in which FGF was specifically blocked in the ectoderm. Spinal cord and hindbrain markers were inhibited in these recombinants, whereas anterior markers and cement gland development were enhanced. Our results demonstrate that FGF is important for posterior development in both mesoderm and neurectoderm and that neural induction and posteriorization represent separable developmental events.

Animals↗
PubMed1999

Cngsc, a homologue of goosecoid, participates in the patterning of the head, and is expressed in the organizer region of Hydra.

We have isolated Cngsc, a hydra homologue of goosecoid gene. The homeodomain of Cngsc is identical to the vertebrate (65-72%) and Drosophila (70%) orthologues. When injected into the ventral side of an early Xenopus embryo, Cngsc induces a partial secondary axis. During head formation, Cngsc expression appears prior to, and directly above, the zone where the tentacles will emerge, but is not observed nearby when the single apical tentacle is formed. This observation indicates that the expression of the gene is not necessary for the formation of a tentacle per se. Rather, it may be involved in defining the border between the hypostome and the tentacle zone. When Cngsc(+) tip of an early bud is grafted into the body column, it induces a secondary axis, while the adjacent Cngsc(-) region has much weaker inductive capacities. Thus, Cngsc is expressed in a tissue that acts as an organizer. Cngsc is also expressed in the sensory neurons of the tip of the hypostome and in the epithelial endodermal cells of the upper part of the body column. The plausible roles of Cngsc in organizer function, head formation and anterior neuron differentiation are similar to roles goosecoid plays in vertebrates and Drosophila. It suggests widespread evolutionary conservation of the function of the gene.

Amino Acid Sequence↗
PubMed1995

Lexical factors in the word-superiority effect.

In the Reicher-Wheeler paradigm, fluent readers can identify letters better when they appear in a word than when they appear in either a pronounceable pseudoword (a lexicality effect) or a single letter (a word-letter effect). It was predicted that if both of these effects involve a lexical factor, then adult acquired dyslexic subjects whose deficit prevents access to visual word form should show disruptions of the normal effects on the Reicher-Wheeler task. The results were that dyslexic subjects as well as matched control subjects showed a lexicality effect; however, while the control subjects showed a normal word-letter effect, the dyslexic subjects showed a reverse letter-superiority effect. Both effects, however, showed a systematic variation: As performance on lexical decision improved, the subjects' performance on words in the Reicher-Wheeler task was better than that for all the other conditions. These subject correlations were replicated by using data from a second lexical decision experiment, which utilized the same words and pseudowords that were used in the Reicher-Wheeler task. In addition, an item analysis showed that the words that the subjects had discriminated correctly in lexical decision showed a significant advantage over those that they had not, as well as an improvement relative to the other conditions. These results suggest that there is a lexical factor underlying the lexicality and word-letter effects, and it is proposed that the abnormal letter-superiority effect can be accounted for as the manifestation of other competing factors.

Adult↗
PubMed1992

Development of lateral interactions in the infant visual system.

The development of lateral inhibitory interactions in the infant visual system, as reflected by the visual-evoked potential (VEP), was studied using a radial, asymmetrical windmill-dartboard stimulus. This contrast-reversing stimulus generates VEP responses with a strong fundamental frequency component and an attenuated second harmonic component (relative to that obtained using a symmetrical stimulus). These two harmonic components reflect distinct phenomena, and appear to be the result of short-range (the fundamental) and long-range (attenuated second harmonic) lateral inhibitory interactions elicited by differential luminance-modulation of contiguous spatial regions. We studied the development of the short- and long-range interactions at 100% and 30% contrast in human infants using both VEP amplitude and phase measures. Attenuation of the second harmonic (long-range interactions) was adult-like by 8 weeks of age while the strength of the fundamental (short-range interactions) was adult-like by 20 weeks suggesting a differential development of long-range and short-range interactions. In contrast, corresponding phase data indicated significant immaturities at 20 weeks of age for both the short- and long-range components.

Contrast Sensitivity↗
PubMed1992

Infant VEP and preferential looking acuity measured with phase alternating gratings.

Previously, infants' grating acuity was found to be temporally tuned, but adults' grating acuity was not. In infants, acuity was higher for gratings phase alternating at 7.5 and 14 reversals/sec than for stationary gratings and gratings alternating at 2.5 or 23 reversals/sec. Also, when preferential looking (PL) and visually evoked potential (VEP) acuity were estimated with phase alternating gratings (14 reversals/sec), the acuity difference between the two techniques was smaller than that obtained when phase alternating gratings were used to estimate VEP acuity and stationary gratings were used to estimate PL acuity. In the present study, it was determined if PL grating acuity was tuned in older children and if the smaller difference between VEP and PL acuity found when infants were tested with phase alternating gratings was independent of temporal rate. Grating acuity in infants older than 2 yr was found to be not tuned, and the smaller difference between VEP and PL grating acuity in infants when both were measured with phase-alternating gratings was not rate dependent. VEP acuity and PL acuity for phase alternating gratings developed at different rates, converging to nearly equivalent levels by 12 mo of age.

Aging↗
PubMed1991

Injected Wnt RNA induces a complete body axis in Xenopus embryos.

Studies in Xenopus have shown that growth factors of the TGF beta and Wnt oncogene families can mimic aspects of dorsal axis formation. Here we directly compare the inductive properties of two Wnt proteins by injecting synthetic mRNA into developing embryos. The results show that Wnt-1 and Xwnt-8 can induce a new and complete dorsal axis and can rescue the development of axis-deficient, UV-irradiated embryos. In contrast, activin mRNA injection induces only a partial dorsal axis that lacks anterior structures. These studies demonstrate that the mechanism of Wnt-induced axis duplication results from the creation of an independent Spemann organizer. The relationship between the properties of the endogenous dorsal inducer and the effects of Wnts and activins is discussed.

Activins↗
PubMed1991

Pre-existent pattern in Xenopus animal pole cells revealed by induction with activin.

Activin, a peptide growth factor related to tumour growth factor-beta, has been implicated in early inductive interactions in vertebrates and can induce Xenopus blastula ectodermal explants to develop a rudimentary axial pattern with anteroposterior and dorsoventral polarity. Here we demonstrate that prospective dorsal and ventral regions of the ectoderm respond differently to the same concentration of activin. Thus, activin does not seem to endow ectodermal cells with polarity but rather reveals a pre-existent pattern. Our results suggest that patterning of mesoderm is determined not only by a localized inducer, but also by the differential competence of cells in the responding tissue.

Activins↗
PubMed1990

Activins are expressed early in Xenopus embryogenesis and can induce axial mesoderm and anterior structures.

We show that mammalian and Xenopus activins induce dorsal axial mesoderm and anterior structures in explants of Xenopus blastula cells that would otherwise form epidermis. The induced explants of animal cap cells can form notochord, muscle, neural tissue, and eyes all arranged in a rudimentary axial pattern. Activin A shares inductive properties and antigenic determinants with PIF, an inducing factor recently isolated from mouse macrophage culture supernatants. Genes encoding Xenopus activin beta A and beta B chains were cloned. Activin beta B transcripts are first detected in Xenopus blastula, whereas activin beta A transcripts do not appear until the late gastrula stage. Recombinant Xenopus activin beta B protein induces mesodermal and neural tissues similar to those induced by mammalian activin A and PIF. Furthermore, ectopic expression of Xenopus activin beta B produces a second body axis in embryos injected with synthetic mRNA. Our results suggest that early induction and axial patterning are accomplished by endogenous activin B, not activin A, in Xenopus.

Activins↗
PubMed1990

A mouse macrophage factor induces head structures and organizes a body axis in Xenopus.

Soluble peptide factors have been implicated as the agents responsible for embryonic inductions in vertebrates. Here, a protein (PIF) secreted by a mouse macrophage cell line is shown to change the developmental fate of Xenopus embryonic cells. Exposure to PIF causes presumptive ectodermal explants to form anterior neural and mesodermal tissues, including brain and eye, instead of ciliated epidermis. In addition, the induced tissues are organized into a rudimentary embryonic axis. These results suggest that PIF or a closely related molecule is involved in inducing anterior structures and organizing the frog body plan.

Animals↗
PubMed1990

A two-step model for the localization of maternal mRNA in Xenopus oocytes: involvement of microtubules and microfilaments in the translocation and anchoring of Vg1 mRNA.

In an effort to understand how polarity is established in Xenopus oocytes, we have analyzed the process of localization of the maternal mRNA, Vg1. In fully grown oocytes, Vg1 mRNA is tightly localized at the vegetal cortex. Biochemical fractionation shows that the mRNA is preferentially associated with a detergent-insoluble subcellular fraction. The use of cytoskeletal inhibitors suggests that (1) microtubules are involved in the translocation of the message to the vegetal hemisphere and (2) microfilaments are important for the anchoring of the message at the cortex. Furthermore, immunohistochemistry reveals that a cytoplasmic microtubule array exists during translocation. These results suggest a role for the cytoskeleton in localizing information in the oocyte.

Actin Cytoskeleton↗
PubMed1989

Localization of mRNA and axis formation during Xenopus embryogenesis.

This paper summarizes our recent work concerned with the developmental polarity of the frog egg and the patterning of the embryonic body plan. In two separate projects, we are studying genes involved in setting up basic embryonic axes. One of these genes, Vg1, codes for a maternal mRNA that is localized in the frog egg. The Vg1 gene is used in studies on the induction of mesoderm and as a probe to understand how the polarity of an egg is established. A second gene, Xhox3, contains a homeodomain and is differentially expressed in the axial mesoderm. Our studies suggest that this homeobox gene is critically involved in setting up different positional values along the anteroposterior axis.

Animals↗